ll Article DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaphthalene Wei-Yi Ding, Peiyuan Yu, Qian-Jin An, ..., Ying Chen, K.N. Houk, Bin Tan [email protected] (K.N.H.) [email protected] (B.T.) HIGHLIGHTS Computation-guided screening of functional groups for arene activation Chemoselective C–H functionalization of 2- nitrosonaphthalene at an unconventional site One-pot synthesis of optically active NOBINs by a solo organocatalytic system Divergent access to two types of axially chiral arylindole frameworks Guided by computational design, Tan and colleagues disclose a chiral phosphoric- acid-catalyzed asymmetric functionalization of naphthalenes with nitroso as the activating and directing group. This nucleophilic aromatic substitution reaction allows divergent access to two types of axially chiral arylindole frameworks with wide substrate generality under excellent enantiocontrol and, more importantly, offers a facile approach to the privileged NOBIN (2-amino-20-hydroxy-1,10- binaphthyl) structures. DFT calculations illustrate the plausible reaction pathway and provide additional insights into the origins of enantioselectivity. Ding et al., Chem 6, 2046–2059 August 6, 2020 ª 2020 Elsevier Inc. https://doi.org/10.1016/j.chempr.2020.06.001 ll Article DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaphthalene Wei-Yi Ding,1,4 Peiyuan Yu,1,4 Qian-Jin An,1,4 Katherine L. Bay,2,4 Shao-Hua Xiang,1,3 Shaoyu Li,1,3 Ying Chen,1 K.N. Houk,2,* and Bin Tan1,5,* SUMMARY The Bigger Picture Functionalization of arenes represents the most efficient approach Highly efficient conversion of for constructing a core backbone of important aryl compounds. inexpensive and readily available Compared with the well-developed electrophilic aromatic substitu- arene materials into high-value- tion and transition-metal-catalyzed C–H activation, nucleophilic aro- added chiral molecules is of great matic substitution remains challenging because of the lack of a importance in modern synthetic convenient route for rapid conversion of the sH adduct to other sta- chemistry given the enormous ble and versatile intermediates in situ. Guided by computational potential of such structures in design, we were able to realize asymmetric nucleophilic aromatic functional materials, substitution by introducing a nitroso group on naphthalene via chi- pharmaceuticals, and other ral phosphoric acid catalysis. This strategy enables efficient con- relevant chemical industries. struction of atropisomeric indole-naphthalenes and indole-anilines Organocatalytic nucleophilic with excellent stereocontrol. Density functional theory (DFT) calcu- aromatic substitution enabled by lations provide further insights into the origins of enantioselectivity an azo group offers an effective and the reaction mechanisms. The successful application in the syn- approach to enantioselective thesis of NOBINs (2-amino-20-hydroxy-1,10-binaphthyl) extends the functionalization of naphthalene utility of this strategy. C–H bonds featuring an intramolecular oxidation of an sH INTRODUCTION unstabilized adduct. Premised on density functional theory (DFT) Functionalized arene frameworks are involved in many reagents, catalysts, materials, calculations, nitroso has emerged 1 and pharmaceuticals. Electrophilic aromatic substitution reactions (via positively as another promising activating 2–4 charged Wheland intermediates), such as the Friedel-Crafts reaction, are the and oxidative group, whose classic approach to substituted arenes (Figure 1A). Recent advances in transition- synthetic potential is metal and photoredox catalysis have enriched the synthetic chemists’ toolbox for substantiated in the 5–11 the functionalization of different arene scaffolds. Functionalizations via the nega- atroposelective synthesis of sX sH tively charged Meisenheimer adduct or adduct often bank on the presence of several groups of representative nitro substituents and nucleofugal halogen (X) or external oxidants (H), which limit biaryl atropisomers processed by 12–14 applicability (Figure 1A). Although it has been established that the formation a chiral phosphoric acid catalyst. sH sX 15 of adductsprecedestheformationof adducts, we recently employed asym- The success of this reaction 16–19 20 sH metric organocatalysis and azo groups to harness the adduct and effi- explicitly exemplifies the ability of ciently enable the functionalization of arenes with bifunctional chiral phosphoric computational tools to streamline 21–23 acid (CPA) catalysis. The azo substituent constitutes extended conjugation organic synthesis with intensified and electron-withdrawing capability to prime the arene for a regioselective nucleo- robustness in the disclosed philic attack (Figure 1B). It further serves as an oxidant to promote expeditious intra- strategy. molecular conversion of the sH adduct intermediate to outcompete the formation of the sX adduct. To further extend this concept and bring about a more universal syn- thetic tool for arene functionalization, one could, in principle, utilize substrates pos- sessing substituents with electronic properties similar to those of the azo group. With the help of electronic structure calculations on a series of naphthalene 2046 Chem 6, 2046–2059, August 6, 2020 ª 2020 Elsevier Inc. ll Article derivatives, we found that a nitroso group exhibits great potential for such a trans- formation (Figure 1C). RESULTS AND DISCUSSION Preliminary Computational Screening On the basis of these considerations, a series of substituted naphthalenes were de- signed and subjected to preliminary computational screening in search of optimal substrate models for catalytic asymmetric nucleophilic aromatic substitution.24–26 We reasoned that the reactivity of arenes toward nucleophilic aromatic substitution might be closely related to the electron affinity (EA) and lowest unoccupied molec- ular orbital (LUMO) energies of the substrates. Therefore, we computed these two simple parameters for a series of substituted naphthalenes. As depicted in Figure 2A, the EA (computed as the energy difference between the neutral molecule and its anionwithonenegativecharge)ofdifferent 2-substituted naphthalenes was first computed at the B3LYP-D3BJ/6-311+G(d,p)/B3LYP/6–31G(d) level. Substrates with nitrogen substituents such as azo (1.72 eV), nitroso (1.50 eV), and nitro (1.41 eV) groups have the highest EA. We next computed the LUMO energy of these sub- strates, another great indicator of their reactivity toward nucleophilic aromatic sub- stitution. More importantly, we evaluated the effect of a simple model phosphoric acid (PA) as well by computing the LUMO of the substrate-PA complexes and comparing it with their original LUMO. For example, coordination of PA with 2-nitro- sonaphthalene through hydrogen-bond interaction would lower the LUMO energy from 0.85 to 0.42 eV (Figure 2B). Hydrogen-bond interactions between the sub- strates and PA would presumably lower its LUMO energy and consequently allow for a more facile nucleophilic aromatic substitution to occur. In addition, with CPA catalysts, the stereochemical outcome could be tuned with judicious choice of cata- lyst scaffolds. The choice of this simple model PA reduced the large conformational space of using more complex CPA catalysts and its associated high computational cost, which allowed us to rapidly screen the effects of different substituents. The screening results are illustrated in Figure 2C, which shows that the nitroso and azo groups are the most promising candidates because of their dramatic decreases in LUMO energy through interactions with PA. The azo group has been verified to be effective for arene functionalization by our recent work.20 Nitrosoarenes,27–29 which are widely used in aminoxylation and hydroxyamination reactions with competitive reactive sites on nitrogen and oxygen atoms, proved to be equally promising. However, as far as we know, the site-selective reaction that occurred on the aromatic ring was rarely realized. With these doubts in mind, we initiated the experiment. Optimizing Reaction Conditions for the Synthesis of Indole-Naphthalene 1Shenzhen Grubbs Institute, Department of Axially chiral skeletons are recognized as the core structure of numerous competent Chemistry, Southern University of Science and ligands or catalysts in asymmetric catalysis for a wide spectrum of useful transforma- Technology, Shenzhen, Guangdong 518055, China tions.30–33 The unique structural features together with the promising chemical and 2Department of Chemistry and Biochemistry, bioactive properties render the construction of axially chiral scaffolds rewarding yet University of California, Los Angeles, Los challenging.34–56 With 2-nitrosonaphthalene (1a) as the promised electrophile, Angeles, CA 90095, USA indole (2a) was selected as the reaction partner for the asymmetric cross-coupling 3Academy for Advanced Interdisciplinary Studies, reaction because of its availability in building atropisomeric molecules. Initially, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China thereactionof1a (0.105 mmol) and 2a (0.1 mmol) was conducted in CH Cl at 2 2 4These authors contributed equally roomtemperature(RT)for1hundertheactivationofCPA(S)-C1 (5 mol %). Intrigu- 5Lead Contact ingly, the expected compound 3a was not detected, and instead, the oxidation *Correspondence: product 4a was obtained in 12% yield with 62% enantiomeric excess (ee). At the [email protected] (K.N.H.), same